TITLE: Antibiotics and Infectious Diseases in Otolaryngology--HNS

SOURCE: Grand Rounds Presentation, UTMB, Dept. of Otolaryngology

DATE: May 8, 2002
RESIDENT PHYSICIAN: Glen T. Porter, MD
FACULTY PHYSICIAN: Francis B. Quinn, MD
SERIES EDITORS: Francis B. Quinn, Jr., MD and Matthew W. Ryan, MD
"This material was prepared by resident physicians in partial fulfillment of educational requirements
established for the Postgraduate Training Program of the UTMB Department of Otolaryngology/Head and Neck
Surgery and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating
group discussion in a conference setting. No warranties, either express or implied, are made with respect to its
accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of
members of the UTMB faculty and should not be used for purposes of diagnosis or treatment without consulting
appropriate literature sources and informed professional opinion."

From the dawn of modern medicine the understanding of infectious disease and how to
treat it has been an integral part of our craft. Many thousands of scientist-physicians struggled to
learn the secrets of the diseases that plagued their patients. Their work brought a new era of
clarity and promise. When penicillin was discovered our world was changed forever. Suddenly,
it was possible not only to diagnose disease and predict it’s course, but to halt it’s progression.
Multiple classes of antibiotics were discovered as the microbiology of disease came into focus.
Medical treatment of disease changed dramatically. Today, a wealth of information is available
to guide the use of antibiotics in infectious disease.

ANTIBIOTICS

The practice of Otolaryngology--HNS requires a clear understanding of many diseases

specific to the head and neck, as well as a thorough knowledge of the antibiotic armamentarium.
The antibiotics are divided into families of drugs that act in a similar ways to attack the bacterial
pathogen. These families include penicillins, cephalosporins, macrolides, aminoglycosides,
sulfonamides, flouroquinolones, and “other” drugs such as vancomycin and clindamycin.

Penicillins are fermentation products of Penicillium mold. The drugs are characterized
by a Beta-lactam nucleus attached to a thiazolidine ring. Different penicillins with different
spectra of effectiveness are created when changes are made to the side chains attached to the
ring. Alteration of the Beta-lactam nucleus results in loss of the compound’s antibiotic potential.
Penicillins act to inhibit bacterial replication by interfering with the final step of cell wall
synthesis. As a result of this action (or perhaps by an other, unknown mechanism) the bacterial
cell’s enzymatic regulatory system is deregulated and lytic enzymes are produced that result in
autolysis. Bacteria that do not have such an enzymatic pathway tend to be more resistant to
penicillin’s action. Thus, penicillins can be either bacteriostatic or bacteriocidal. The penicillins
are excreted in their original form by the kidney. The drug Probenecid has been used to slow
excretion allowing for higher and longer serum drug concentration. Most penicillins are
destroyed by stomach acid, thus they should be taken on an empty stomach. Tissue penetration
is generally good. Antibiotic concentrations are generally higher in areas of inflammation and
enable CSF and middle ear penetration.
 Many patients report they are “allergic” to penicillins. Hypersensitivity is known to
occur in approximately 5% of the population. A rash is the most common reaction. This
symptom may be treated with antihistamines, but usually results in discontinuing the antibiotic.
This may recur in only 50% of patients with repeated exposure. Penicillin-induced rash in the
face of mononucleosis is not a contraindication for further use. Only 5% of patients who are
sensitive to penicillin can be expected to be sensitive to cephalosporin antibiotics. Anaphylaxis
is a rare occurrence (1 in 10,000) is more common with IV dosing. Beta-lactam antibiotics
(cephalosporins and carbepenems) should not be used in penicillin-allergic patients unless there
are no other good alternatives. Penicillin desensitivization can be undertaken with the patient in
the intensive care unit under continuous monitoring.

B-lactam antibiotic use has led to the emergence of multiple resistant strains of bacteria.
There are several methods for bacteria to become resistance to the antibiotic’s effects. Intrinsic
resistance is the particular makeup of the bacteria which prevents drug binding of cell proteins or
penetration of the cell wall. This likely accounts for the penicillins’ lack of activity against
Legionella, Mycobacterium, fungi, Chlamydia, and rickettsia families. Production of enzymes
that inactivate penicillin is the most common method of resistance. It is propagated via plasmid
or chromosome transmission. Beta-lactamase and penicillinase are enzymes produced by
resistant bacteria that cleave the beta-lactam ring and inactivate penicillins. These enzymes have
been shown to be produced by H. influenzae, M. catarrhalis, S. aureus, many anaerobes and
gram-negative organisms. Penicillinase is specific to S. aureus. Resistant S. aureus is especially
virulent as it proliferates the enzyme and releases it into the milieu. This destroys the antibiotic
before it reaches the cell and provides protection for any other sensitive organisms in the
vicinity. Of note, penicillinase is not effective against the semisynthetic (antistaphylococcal)
penicillins or cephalosporins. S. pneumoniae resistance is entirely different and is mediated by
alteration in cell binding sites. Intermediately-resistant strains are still sensitive to higher
concentrations of antibiotic.

Antistaphylococcal penicillins are semisynthetic penicillins which have been found to be

especially effective against penicillin-resistant S. aureus or S. epidermidis infections. (S. aureus
resistant to this group of drugs is known as “methicillin-resistant S. aureus” (MRSA) and is
resistant to all penicillins). This class includes methicillin, oxacillin, cloxacillin, dicloxacillin,
nafcillin. Of these antibiotics, dicloxacillin achieves the highest serum levels. These drugs are
generally less effective against organisms that are penicillin sensitive. These antibiotics are
commonly used when skin flora are the suspected pathogens.

The aminopenicillins have an extended spectrum when compared with penicillin. This
class includes ampicillin, amoxicillin, and becampcillin. They cover all bacteria sensitive to
penicillin (pneumococcal, streptococcal, actinomycosis, and about half of the anaerobic
organisms of the oral and upper respiratory tract) as well as increased efficacy in treating
resistant Streptococci, pneumococcus (except highly-resistant), H. influenzae (5-55% of cultured
strains currently found to be resistant), Proteus, and many coliforms. These drugs are typically
less effective against beta-lactamase (and penicillinase) producing microbes. Ampicillin, when
given per os, is destroyed by stomach acid. Amoxicillin and becampicillin, however, may be
taken at mealtime. Serum and middle ear levels are highest with these agents. There is evidence
that high levels of amoxicillin can be effective against intermediate-resistant S. pneumo. The
side effect profile is somewhat different for these antimicrobials. They generally cause much
more diarrhea and may cause rash in 50% of patients with mononucleosis who are treated with
amoxicillin. Yogurt or Bacid is often prescribed concurrent with aminopenicillins in an attempt
to ameliorate the GI side effects.

The augmented penicillins include amoxicillin + clavulanate (Augmentin), ampicillin +

sulbactam (Unasyn), Ticarcillin + clavulanate (Timentin), Piperacillin + tazobactam (Zosyn).
The additives are substances that are weakly antimicrobial by themselves, but when combined
with a penicillin serve to irreversibly bind the beta-lactamase enzyme. This action reverses
resistance trends in H. influenzae, M. catarrhalis, S. aereus, and B. fragilis. The augmented
ticarcillin and piperacillin add pseudomonas coverage. As pneumococcal resistance is mediated
by penicillinase (not a beta-lactamase) the augmented penicillins are no more effective against
penicillin-resistant S. pneumoniae. The side effects are similar to those of the aminopenicillins.

The antipseudomonas penicillins include ticarcillin, mezlocillin, and piperacillin. These

drugs are less active against gram-positive bacteria than are the aminopenicillins. Despite their
extended spectrum, they are inactivated by beta-lactamase and therefore offer no advantage over
other penicillins for non-pseudomonas infections. Synergy has been noted when
antipseudomonas penicillins are combined with aminoglycosides. Ticarcillin is known to cause
platelet dysfunction and may exacerbate congestive heart failure with it’s high NaCl content.

Cephalosporins are semisynthetic beta-lactam antimicrobials which are derived from

Cephalosporium acremonium. Their mechanism of action is essentially the same as that of
penicillin. Resistance to cephalosporins is mediated by enzymes that destroy the beta-lactam
core. The chemical structure of this drug makes it less susceptible to penicillinase. These drugs
achieve wide distribution in the body, but do not cross the blood-brain barrier even in the setting
of meningeal inflammation (some of the later generation agents are exceptions to this).
Cephalosporins are metabolized in the liver and excreted by the kidney. As with penicillin,
Probenecid may be used to increase serum levels and decrease kidney excretion. This is
accomplished by competing for protein binding sites and decreasing tubular secretion. The
broad spectrum of this class can lead to opportunistic bacterial/yeast/fungus overgrowth
(candidiasis, C. difficile infections). Non-Clostridium diarrhea is also common. The
cephalosporins are subdivided into “generations” which are grouped according to their spectrum.
In general, the earlier generations cover most gram-positive bacteria and few gram-negative
organisms. Later generations cover progressively more gram-negative and fewer gram-positive
bacteria.

The first generation agents include cefadroxil, cefazolin, cephallexin. Their spectrum
includes most gram-positive cocci (GAS, S. pneumo., S. aureus (except MRSA which is resistant
to all cephalosporins), as well as gram-negatives like E. coli, Proteus, and Klebsiella. These
drugs are commonly used for treatment of S. aureus infections and for surgical prophylaxis (skin
flora).

Second generation cephalosporins are effective against the bacteria commonly found in
otitis media and sinusitis, including ampicillin-resistant H. influenzae and intermediate-resistant
S. pneumo. They generally have good CSF penetration. 2nd generation equivalents from the 3rd
generation include defpodoxime (Vantin), defdinir (Omnicef). Their activity is equivalent to
cefuroxime (Ceftin) and can all be used as an alternative to Augmentin. It is less effective
against S. aureus than the 1st generation cephalosporins.

Third generation cephalosporins cover more gram-negative bacteria than the earlier
classes, but loose much of their effectiveness against gram-positive microbes. They are
especially useful in identified beta-lactimase positive H. influenzae infections, as well as against
M. catarrhalis, N. gonorrhea, and N. meningitidis. Ceftriaxone (Rocephin) and ceftotaxime
(Claforan) are effective against S. pneumo. (even highly-resistant forms), as well as H.
influenzae, and N. meningitidis. These agents can be used against high-level, multi-drug
resistant pneumococcal infections in combination with Vancomycin. A single dose of Rocephin
(IM) has been shown effective in common otitis media. Ceftazidime (Fortaz) is the most
effective of all beta-lactam antibiotics against P. aeruginosa and is considered an alternative to
Gentamicin.

The carbipenem class includes imipenem-cilastin (Primaxin) and meropenem (Merrem).

These are broad-spectrum beta-lactam antibiotics which cover nearly all bacteria with the
exception of MRSA and C. difficile. Side effects include hypersensitivity reactions and seizures.
Meropenem is considered less prone to cause seizure activity. These drugs are useful in critical
patients with serious mixed infections. Aztreonam (Azactam) is a mono-bactam antibiotic that
can be used in penicillin-allergic patients for gram-negative infections and can be substituted for
aminoglycosides.

Macrolides are derived from Streptomyces erythreus (erythromycin is a natural product).

These drugs bind the 50s subunit of bacterial ribosomes which results in inhibition of protein
synthesis. Microbes develope resistance by altering target sites, altering the antibiotic, or
changing transfer kinetics. Macrolides are especially useful for their excellent penetration of
oropharyngeal secretions and tissues. These drugs are effective in the treatment of atypical
infections (Chlamydia, Mycoplasma), Staphylococcal infections (MRSA is resistant), Strep.
(including resistant strains), Bordetella pertussis, H. influenzae, and M. catarrhalis. Their
spectrum makes them useful in treating GAS pharyngitis, AOM with resistant bacteria, and
sinusitis. Bactrim, clarithromycin, and azithromycin are all as effective as Augmentin in the
treatment of AOM. Clarithromycin has been shown to have equal efficacy to that of Augmentin
in sinusitis, but necessitates just as long a course (10-14 days). Azithromycin is a good
alternative for treating sinusitis as it requires only a 3-5 day course (500mg per day). Side
effects are rare with macrolide use. Ototoxicity has been documented with prolongued use and
high peak levels.

Clindamycin is derived from Streptomyces Lincolnensis. The mechanism of action, like

the macrolide class, is inhibition of protein synthesis by binding to the 50s ribosomal subunit. It
has a wide distribution, but does not cross the blood-brain barrier. The drug is concentrated in
the bone, respiratory tissues, mucus, and saliva. The oral form results in only 25-50% of serum
levels when administered perenterally. At lower concentrations the drug is bacteriostatic, but
bacteriocidal at higher concentration. Resistance is mediated by decreased permeability of the
drug into the cell and alteration of binding sites on the 50s ribosome subunit. Side effects
include nausea/vomiting, and pseudomembranous colitis. The spectrum of action is primarily
against gram-positive bacteria and anaerobes (especially B. fragilis). It has little activity against
gram-negative microbes. The drug is useful in chronically draining ears, contaminated neck
wounds, chronic tonsillitis and deep neck abscesses. It is superior to penicillin in clearing
pharyngitis/tonsillitis. Some strains of MRSA are sensitive to clindamycin.

Vancomycin is a glucopeptide produced by Streptomyces Orientalis. It is bacteriocidal

and acts by inhibiting cell wall replication. Parenteral vancomycin is eliminated by the kidneys.
The oral form is not absorbed and is primarily for treatment of C. difficile. Vancomycin is a
highly-effective agent to treat gram-positive infection. It is one of the few antibiotics that have
activity against MRSA, and multi-drug resistant, highly-resistant Pneumococci. When used in
combination with gentamicin there is a notable synergy in addition to increased risk of
ototoxicity. Side effects include red-man syndrome (chills, fever, rash and flushing) and
development of resistant enterococcus.

Metronidazole (Flagyl) is an important antibiotic that provides significant efficacy in

treating anaerobic and parasitic infections. The mechanism of action includes intracellular
chemical reactions that produce DNA-toxic substances within the cell resulting in bacteriocidal
effect. Metronidazole reaches good levels in nearly all body tissues, including the CSF, saliva,
bone, and abscesses. Bioavailability studies show equal efficacy with oral and intravenous
dosing. The oral form is used to treat C. difficile colitis. Other uses include deep neck
infections, brain abscesses or difficult anaerobic infections. Side effects can include nervous
system deficiencies, but are rare. When taken with alcohol the drug results in a disulphram-like
effect.

Aminoglycosides are produced by Streptomyces and Micromonospora species. They act

by binding to ribosomes and interfering with bacterial protein synthesis. They are bacteriocidal.
These drugs are given IM or IV, though parenteral administration gives more consistent and
higher serum drug levels. Aminoglycosides have poor penetration into CSF, but cross the
placenta. They are excreted, unchanged, in the urine. These antimicrobials are effective in the
treatment of gram-negative bacilli, especially P. aeruginosa. Resistance is mediated via bacterial
enzymes that modify the antibiotic resulting in the inability to bind to the target ribosomes.
Toxicities include damage to the kidneys (elevated trough levels), inner ear (concentrated in
perilymph with prolonged use and elevated peak levels), and neuromuscular blockade.

Sulfonamides are effective against H. influenzae, and M. catarrhalis, but generally not
effective against other microbes. It is often combined with other antibiotics. When combined
with erythromycin (Pediozole) is it as effective as ampicillin in the treatment of otitis media.
Bactrim is the combination of a sulfonamide with trimethoprim. These drugs act at different
points of the protein synthesis chain. Used together, their actions are synergistic. Bactrim is
more effective against beta-lactamase producing H. influenzae and M. catarrhalis than
ampicillin. Sulfa allergies can result in life-threatening reactions (TENS).

Flouroquinolones are broad spectrum antibiotics effective against gram-positive bacteria,

gram-negative bacteria, atypical bacteria, and pseudomonas. Ciprofloxacin is the most effective
oral agent to treat P. aeruginosa. Ciprofloxacin and ofloxacin ototopicals are extremely effective
in treatment of mastoiditis and otitis media (via PET). Ototoxicity is not a part of the side effect
profile. Levofloxacin is active against GAS, S. pneumo. (including penicillin-resistant strains),
S. aureus (including MRSA), H. influenzae, and M. catarrhalis (including beta-lactamase
producing strains). The newer flouroquinolones show a spectrum similar to levofloxacin, but
with increased anaerobic and decreased pseudomonas coverage. The flouroquinolones are well
absorbed by mouth (bioavailability is equal to that of parenteral dosing) with wide distribution,
including the CSF. It is long-acting and requires only once-a-day dosing. Side effects include
drug interactions, tendon toxicity, and questionable bone growth impairment (animal studies
only).

SELECTED INFECTIOUS DISEASES

Rhinosinusitis is one of the most common medical problems in America. The

mechanism for this disease is thought to be the blockage of the osteomeatal complex leading to
stasis of nasal secretions and subsequent infection. First line treatment for simple rhinosinusitis
is similar to that of otitis media (amoxicillin/Bactrim) as the same microorganisms are
implicated—S. pneumo., M. catarrhalis, and H. influenzae. Second line antibiotics include
Augmentin, clarithromycin, cefuroxime, Pediazole. Adjuvant therapies can include nasal
irrigation, nasal steroids (shown to increase effectiveness of antibiotics), and decongestants. One
study looking at the differences in outcome, etc. between first and second-line antibiotics was the
cost of the treatments. Chronic sinusitis is characterized by a mixture of microorganisms,
including anaerobes. Treatment is best undertaken with clindamycin or Augmentin. Polyposis
often cultures positive for P. aeruginosa and is therefore commonly treated with Cipro or other
antipseudomonas drugs. Finally, patients with recurrent sinusitis after FESS have been shown to
grow a wide variety of microbes (37.9% gram-positive cocci, 14.8% gram-negative rods, and
1.7% fungal elements, 30% negative cultures). Pseudomonas was isolated in 7.2% of cultures
and 12% of these were resistant to Cipro. 90% of patients that grew gram-negative bacteria were
noted to have multiple recurrent infections. Given the spectrum of possible agents in FESS
patients, it is wise to implement culture-directed antibiotic therapy. Topical antimicrobials have
also been shown to be of some use, though this is still under study. Hypertonic saline irrigations
have also been shown to be effective treatment in patients with patent ostia.

Pharyngitis is most commonly of concern when it is caused by Group A Streptococcus

(GAS). GAS is the most common bacterial cause of this acute pharyngitis (15-30% in children,
5-10% in adults). Physical examination often reveals tonsillopharyngeal exudates (though not as
florid as with Mono) with anterior cervical lymphadenitis. Treatment traditionally has called for
penicillin/erythromycin as first line treatment (still shown effective in patients >12 years old or
ill for >2 days). The advent of increasingly resistant organisms have resulted in
recommendations for use of a second generation cephalosporin or clindamycin. This argument is
based on two hypotheses: beta-lactamases proliferated by S. aureus and other resistant
organisms may inactive penicillin before it is able to have effect against GAS; or normal flora
(alpha-streptococci) is decimated by penicillins, but are preserved by cephalosporins.
Diphtheria, though rare, can also cause pharyngitis. Viral infections are likely responsible for
the majority of all cases of pharyngitis. Infectious mononucleosis is an important entity. It is
caused by the Epstein-Barr virus and affects 15-24 year-old patients predominately. The disease
is characterized by a prodrome followed by sore throat, high fever and lymphadenitis (often
pronounced). Splenomegaly is seen in 50% of patients. Treatment is supportive with care taken
to avoid prescribing amoxicillin which causes rash in 50% of patients with Mononucleosis.
 Otitis media has been the subject of multiple studies and continues to be a topic of
considerable discussion. Three bacteria are primarily responsible for middle ear infections.
These include Strept. pneumonea, M. catarrhalis, and H. influenzae. In recent studies of large
numbers of children S. pneumoniae showed resistance to penicillin in 5-61% of patients, H.
influenza showed 5-55% resistance to amoxicillin, and M. catarrhalis showed >75% resistance to
all penicillins. Recommended treatment is amoxicillin (80-90mg/kg/day as higher doses seem to
overcome some resistance patterns) or Bactrim (penicillin-allergic). Second-line agents
(Augmentin, ceftriaxone, quinolones) should be used if one is practicing in an area of high
resistance, or after failure of a first-line agent. Serious otologic infections should be treated with
vancomycin. If the infection is involving areas that are poorly penetrated by vancomycin (i.e.
CSF), cefotaxime or ceftriaxone should be added. Prophylaxis has been evaluated for those with
recurrent infections. A recent study showed that prophylaxis with amoxicillin (once-daily
dosing) decreased the incidence of MEE, AOM, and OME without evidence of bacterial
resistance. Several recent meta-analyses have shown questionable efficacy of antibiotic
treatment for AOM in children. These studies are flawed by differing entrance criteria and
definitions of resolution—most authors feel they do not provide convincing evidence. Most
agree that the serious complications of untreated AOM necessitate active treatment of this
disease.

Suppurative otitis is often associated with chronic ear disease. In one study cultures grow
27% P. aeruginosa, and 24% S. aureus. Proteus and fungal agents have also been identified.
Treatment is debridement followed by ototopical antimicrobials. Ototopicals that cover
Pseudomonas and S. aureus are indicated. These include polymyxin (or gent) with neomycin, or
cipro/ofloxacin (good for use with TM that is not intact). Aspergillis fungal otitis externa can be
treated with topical acetic acid (ototoxic), boric acid, merthiolate, iodine, or gentian violet
(ototoxic). Topical Lotrimin (clotrimazole) is used for candidiasis.

Sialedenitis can be caused by different organisms depending on which gland is involved.

One study cultured drainage from acutely infected salivary glands. Their results helped to clarify
the microbiology of acute suppurative sialedenitis. Their results showed:

Anaerobic Aerobic Mixed

Parotid 41% 35% 25%
Submaxillary 33% 44% 22%
Sublingual 33% 33% 33%

The most common aerobes isolated were S. aureus and H. influenzae. The anaerobes
were predominately gram-negative bacilli. Antimicrobial treatment for acute sialedenitis may
include Augmentin, clindamycin, or a cephalosporin combined with metronidazole.

Deep neck abscesses are usually caused by a mixture of organisms which may
include anaerobes, Staph, Strept., and Pseudomonas. Treatment is incision and drainage
followed by clindamycin and gentamicin, or ceftazidime combined with metronidazole.

Bacterial resistance to antibiotics has become and increasing problem in the era of “big
gun” antibiotics and patients who expect a prescription for every illness. Precise use of
antibiotics is seldom practiced as physicians opt for drugs that will cover “everything.”
Moreover, doctors often find themselves treating illnesses that are likely not bacterial. These
factors have created a evolutionary pressure that has resulted in the most common pathogens of
otitis media, sinusitis, and pharyngitis developing resistance to antibiotics that were extremely
effective just 10-20 years ago. The development of MRSA, VRE, and the like may very well be
precursors to a time when there will be infections we cannot treat with antibiotics. If we are to
avoid a return to the time when we must stand helpless against infectious disease we must
understand the illnesses we diagnose and treat them appropriately.

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